Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3Y35CV)

DOT Name Sodium bicarbonate cotransporter 3 (SLC4A7)
Synonyms Electroneutral Na/HCO(3) cotransporter; Sodium bicarbonate cotransporter 2; Sodium bicarbonate cotransporter 2b; Bicarbonate transporter; Solute carrier family 4 member 7
Gene Name SLC4A7
Related Disease
Cone-rod dystrophy ( )
UniProt ID
S4A7_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF07565 ; PF00955
Sequence
MERFRLEKKLPGPDEEAVVDLGKTSSTVNTKFEKEELESHRAVYIGVHVPFSKESRRRHR
HRGHKHHHRRRKDKESDKEDGRESPSYDTPSQRVQFILGTEDDDEEHIPHDLFTEMDELC
YRDGEEYEWKETARWLKFEEDVEDGGDRWSKPYVATLSLHSLFELRSCILNGTVMLDMRA
STLDEIADMVLDNMIASGQLDESIRENVREALLKRHHHQNEKRFTSRIPLVRSFADIGKK
HSDPHLLERNGEGLSASRHSLRTGLSASNLSLRGESPLSLLLGHLLPSSRAGTPAGSRCT
TPVPTPQNSPPSSPSISRLTSRSSQESQRQAPELLVSPASDDIPTVVIHPPEEDLEAALK
GEEQKNEENVDLTPGILASPQSAPGNLDNSKSGEIKGNGSGGSRENSTVDFSKVDMNFMR
KIPTGAEASNVLVGEVDFLERPIIAFVRLAPAVLLTGLTEVPVPTRFLFLLLGPAGKAPQ
YHEIGRSIATLMTDEIFHDVAYKAKDRNDLLSGIDEFLDQVTVLPPGEWDPSIRIEPPKS
VPSQEKRKIPVFHNGSTPTLGETPKEAAHHAGPELQRTGRLFGGLILDIKRKAPFFLSDF
KDALSLQCLASILFLYCACMSPVITFGGLLGEATEGRISAIESLFGASLTGIAYSLFAGQ
PLTILGSTGPVLVFEKILYKFCRDYQLSYLSLRTSIGLWTSFLCIVLVATDASSLVCYIT
RFTEEAFAALICIIFIYEALEKLFDLGETYAFNMHNNLDKLTSYSCVCTEPPNPSNETLA
QWKKDNITAHNISWRNLTVSECKKLRGVFLGSACGHHGPYIPDVLFWCVILFFTTFFLSS
FLKQFKTKRYFPTKVRSTISDFAVFLTIVIMVTIDYLVGVPSPKLHVPEKFEPTHPERGW
IISPLGDNPWWTLLIAAIPALLCTILIFMDQQITAVIINRKEHKLKKGAGYHLDLLMVGV
MLGVCSVMGLPWFVAATVLSISHVNSLKVESECSAPGEQPKFLGIREQRVTGLMIFILMG
LSVFMTSVLKFIPMPVLYGVFLYMGVSSLKGIQLFDRIKLFGMPAKHQPDLIYLRYVPLW
KVHIFTVIQLTCLVLLWVIKVSAAAVVFPMMVLALVFVRKLMDLCFTKRELSWLDDLMPE
SKKKKEDDKKKKEKEEAERMLQDDDDTVHLPFEGGSLLQIPVKALKYSPDKPVSVKISFE
DEPRKKYVDAETSL
Function
Electroneutral sodium- and bicarbonate-dependent cotransporter with a Na(+):HCO3(-) 1:1 stoichiometry. Mediates the sodium-dependent bicarbonate transport important for pH recovery after acid load as well as for regulation of steady-state pH in the duodenum and vascular smooth muscle cells. Plays a key role in macrophage acidification, mediating bicarbonate import into the cytoplasm which is crucial for net acid extrusion and maintenance of cytoplasmic pH during phagocytosis. Provides cellular bicarbonate for de novo purine and pyrimidine synthesis and is a key mediator of de novo nucleotide synthesis downstream of mTORC1 signaling in proliferating cells ; [Isoform 6]: Plays a key role in macrophage acidification, mediating bicarbonate import into the cytoplasm which is crucial for net acid extrusion and maintenance of cytoplasmic pH during phagocytosis.
Tissue Specificity Highly expressed in testis and spleen. Also expressed in retina, colon, small intestine, ovary, thymus, prostate, muscle, heart and kidney.; [Isoform 1]: Expressed in skeletal muscle and heart muscle.
Reactome Pathway
RHOD GTPase cycle (R-HSA-9013405 )
RHOQ GTPase cycle (R-HSA-9013406 )
RHOH GTPase cycle (R-HSA-9013407 )
RHOJ GTPase cycle (R-HSA-9013409 )
RHOF GTPase cycle (R-HSA-9035034 )
Bicarbonate transporters (R-HSA-425381 )

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Cone-rod dystrophy DISY9RWN Limited Autosomal recessive [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
25 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [2]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [3]
Tretinoin DM49DUI Approved Tretinoin affects the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [4]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [5]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [6]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [7]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [8]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [9]
Quercetin DM3NC4M Approved Quercetin increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [10]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [11]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [12]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [13]
Marinol DM70IK5 Approved Marinol increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [14]
Selenium DM25CGV Approved Selenium decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [15]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [16]
Testosterone enanthate DMB6871 Approved Testosterone enanthate affects the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [17]
Dihydrotestosterone DM3S8XC Phase 4 Dihydrotestosterone increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [18]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [12]
Tamibarotene DM3G74J Phase 3 Tamibarotene affects the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [4]
Tocopherol DMBIJZ6 Phase 2 Tocopherol decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [15]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [19]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide increases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [20]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [22]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [16]
Nickel chloride DMI12Y8 Investigative Nickel chloride decreases the expression of Sodium bicarbonate cotransporter 3 (SLC4A7). [23]
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⏷ Show the Full List of 25 Drug(s)
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Sodium bicarbonate cotransporter 3 (SLC4A7). [21]
Coumarin DM0N8ZM Investigative Coumarin affects the phosphorylation of Sodium bicarbonate cotransporter 3 (SLC4A7). [21]
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References

1 Novel mutation in SLC4A7 gene causing autosomal recessive progressive rod-cone dystrophy. Ophthalmic Genet. 2020 Aug;41(4):386-389. doi: 10.1080/13816810.2020.1783691. Epub 2020 Jun 29.
2 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
3 Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
4 Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
5 Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. Toxicol Lett. 2016 Jan 5;240(1):50-9.
6 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
7 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
8 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
9 Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
10 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
11 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
12 Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
13 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
14 Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
15 Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
16 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
17 Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
18 LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
19 Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets. Toxicology. 2011 Nov 28;290(1):50-8.
20 Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
21 Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
22 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
23 The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.